Levels of the synaptic proteins PSD‐95, SNAP‐25, and neurogranin are selectively increased in the cerebrospinal fluid of patients with Alzheimer’s disease

Abstract

AbstractBackgroundSynaptic dysfunction and loss occur early in Alzheimer’s Disease (AD) dementia and are closely linked to cognitive decline. Levels of both pre‐ and post‐synaptic proteins are reduced in AD brains while recent studies have shown increased levels of synaptic proteins in the cerebrospinal fluid (CSF) already in the early stages of AD, presumably due to release from degenerating synapses. We measured CSF levels of the novel post‐synaptic marker PSD‐95 together with levels of SNAP‐25 (pre‐synaptic) and neurogranin (post‐synaptic), two emerging synaptic biomarkers, in subjects with AD, other neurodegenerative diseases (OND), and controls.MethodCSF samples from 158 patients undergoing diagnostic lumbar punctures were selected from banked samples. Clinical diagnoses were established by chart review and AD status was verified by CSF ATN biomarkers. 30 subjects had mild cognitive impairment or dementia due to AD, 69 had OND, and 59 were neurological controls (NC). In addition, 30 CSF samples were obtained from healthy subjects (HC) participating in a research study. Levels of PSD‐95 and SNAP‐25 were measured by Quanterix SIMOA assays and neurogranin by an automated Euroimmun ELISA assay.ResultAll subjects had detectable CSF levels of PSD‐95, SNAP‐25, and neurogranin. Levels of all three synaptic markers were higher in AD subjects compared to subjects with OND (p=0.04, p<0.001, and p<0.001, respectively) and both control groups, while levels of SNAP‐25 and neurogranin were lower in OND subjects compared to NC (p=0.005, and p=0.025, respectively). There were tight correlations between levels of PSD‐95, SNAP‐25, and neurogranin with the strongest correlation between SNAP‐25 and neurogranin (r=0.87; r2=0.76; p<0.0001).ConclusionOur data suggest that PSD‐95 and other emerging synaptic markers are selectively increased in the CSF of subjects with AD and that levels of both pre‐ and post‐synaptic markers are tightly correlated. Specific biomarkers for AD‐associated synaptic pathology may hold promise to discriminate AD from other neurodegenerative disorders, to correlate with cognitive decline, and to monitor responses to disease‐modifying drugs reducing synaptic degeneration.